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AbstractAs a kind of glycoside, pentacyclic triterpenoid saponins have good biological activities, such as anticancer, antibacterial, antiviral and hypoglycemic effects [1]. In this paper, twenty-four pentacyclic triterpenoid derivatives, including twelve monosaccharide derivatives, were designed and synthesized. The anticancer effect and antibacterial activities of all compounds were evaluated. It is noteworthy that compound UA-2b has the strongest inhibitory effect on the growth of A549, Hela and HepG2 cancer cells (IC50 = 5.37 ± 0.22 µM, 5.82 ± 0.25 µM and 5.47 ± 0.06 µM, respectively). Compounds OA-2b, OA-6a, OA-6b, UA-2b and UA-6a have the best activity against Escherichia coli 1924 (MIC = 16 μg/ml). [ABSTRACT FROM AUTHOR]

Nine polyacetylenes, including five new compounds named sadivaethynes E -I (1 – 5), were isolated from the roots of Saposhnikovia divaricata. Structural elucidation of compounds 1 – 5 was established by extensive spectroscopic analysis, quantum chemical calculations and DP4+ probability analysis. Among them, the absolute configuration of compound 1 – 2 , 4 – 5 was unambiguous determined by ECD. Also, all compounds were evaluated for cytotoxicity against two human cancer cell lines (A549, HEPG2) in vitro, compound 9 showed moderate inhibitory effect with an IC 50 value of 11.66 μM against HEPG2. [Display omitted] • Five undescribed compounds were isolated from the roots of Saposhnikovia divaricata. • The structures were characterized chemically by NMR, quantum chemical calculations and CD data analysis. • Compound 9 showed moderate inhibitory effect with an IC 50 value of 11.66 μM against HEPG2. [ABSTRACT FROM AUTHOR]

Five new sesquiterpenoids, dictamtrinorguaianols E and F (1–2), and dictameudesmnosides F, G, and H (3–5), along with seven known sesquiterpenoids (6–12) were isolated from Dictamnus dasycarpus Turcz. The structures of all new compounds were characterized by spectroscopic methods, including UV, IR, HR-ESI-MS, and 1D and 2D NMR. The In-vitro anti-proliferative activities of all the compounds against two human cancer cell lines (SW982 and A549) were evaluated by CCK-8 assay. Compounds 1 and 4 showed medium anti-proliferative activity against SW982 cells, with IC 50 values of 3.49 ± 0.10 and 6.42 ± 1.23 μM, respectively. Additionally, compounds 2 , 7 , and 8 exhibited medium anti-proliferative activity against A549 cells, with IC50 values ranging from 0.80 ± 0.05 to 6.60 ± 0.46 μM. [Display omitted] [ABSTRACT FROM AUTHOR]

The article titled "Retraction Note: A New Porous Metal–Organic Framework Constructed from 2, 5-Thiophenedicarboxylate and Melamine Ligands: Catalysis Dye Degradation and Anti-tumor Activity in Myocardioma" has been retracted by the Editor-in-Chief and the Publisher of the Journal of Cluster Science. The retraction was prompted by evidence of systematic manipulation of the publication process, including issues with citations, phrasing, figures, and ethics approval statements. The authors have not responded to correspondence regarding the retraction. Springer Nature, the publisher, remains neutral in regards to jurisdictional claims and institutional affiliations. [Extracted from the article]

Six positional isomers of triptolide–glucose conjugates (TG1α, TG1β, TG2, TG3, TG4 and TG6) were designed and synthesized. These conjugates exhibited better water solubility, and had selective cytotoxicity between tumor cells with high expression of glucose transport-1 (Glut-1) and non-tumor cells with low expression of Glut-1, in which TG2 formed by triptolide (TPL) and d -glucose C2–OH had the strongest cytotoxicity to tumor cells and lowest toxicity in non-tumor cells, therefore the highest relative therapeutic index, which was 5.7 times that of triptolide and consequent the most powerful selective antitumor activity in vitro. The cytotoxicity of TG2 was highly correlated with Glut-1 function. As a prodrug of triptolide, TG2 could promote RNA Pol II degradation and induce apoptosis as TPL does. TG2 had a stronger dose-dependent antitumor effect in vivo than TPL and no adverse reaction occurred when its tumor inhibition was higher than 90%, which was associated with its selective distribution in tumor tissues. TG2 could be used as a promising drug candidate for the treatment of solid tumors with high expression of Glut-1, which is worthy of further study. [Display omitted] TG2 conjugated by triptolide and d -glucose C2–OH has a stronger selective antitumor activity than triptolide due to selective transport of TG2 into tumor cells via glucose transporters. • ●Triptolide-Glucose Conjugate TG2 formed by triptolide C14–OH and d -glucose C2–OH. • ●The cytotoxicity of TG2 is highly dependent on Glut-1 function. • ●TG2 distributes in tumor selectively and has a highly selective antitumor activity. [ABSTRACT FROM AUTHOR]

• A new derivative of podophyllotoxin (GHGT-17) was synthesized by incorporation of cyclopropyl, formyl, piperazinyl groups. • GHGT-17 exhibits significant cytotoxicity against a variety of cancer cells. • The IC 50 of GHGT-17 was less than 100 nM against A549 and H460 cells and greater than 100 µM against 16HBE cells. • In silico ADMET analysis suggests GHGT-17 is unlikely to toxic to normal organs. • Molecular docking study indicates that GHGT-17 could directly bind to the colchicine binding pocket of tubulin. Podophyllotoxin (PPT) is a naturally occurring lignan extracted from the rhizomes of the Podophyllum plant. It exhibits toxicity towards a broad spectrum of cancer cells and can induce cell death by inhibiting the polymerization of microtubule proteins. In our pursuit of more potent anticancer drug candidates, 4α-(cyclopropyl formylpiperazinyl)-4-deoxypodophyllotoxin (GHGT-17) was successfully synthesized by introducing a piperazine group, formyl group, and cyclopropyl group at the C-4 position of PPT. The activity of GHGT-17 against various types of cancer cells was evaluated using the MTT assay. It exhibited significant potency against lung cancer cells, with IC 50 values of 0.080 ± 0.020 μM (A549) and 0.086 ± 0.004 μM (H460), without obvious toxicity towards lung epithelial cells 16HBE (IC 50 > 100 μM). Further investigations demonstrated that GHGT-17 induced morphological changes in A549 and H460 cells, inhibited proliferation in a time- and dose-dependent manner. Furthermore, GHGT-17 inhibited the formation of cell colonies in a dose-dependent manner. It was found to inhibit cell migration, arrest the cell cycle in the G2/M phase, induce nuclear wrinkling, decrease mitochondrial membrane potential, and inhibit microtubule protein polymerization. These effects ultimately contribute to the induction of endogenous apoptosis. In silico studies, ADMET analysis revealed that GHGT-17 exhibited a satisfactory bioavailability with good water solubility, easy absorption, and well-proportioned distribution in the body. Molecular docking was performed to predict the binding mode and interactions of GHGT-17 with tubulin protein (1SA0). Additionally, GHGT-17 was submitted to molecular dynamics simulation and RMSD, RMSF, Rg, hydrogen bonding was analyzed. The complex showed a rather low binding free energy (−36.37 kJ mol−1) and thus exhibited a superior binding affinity towards to tubulin protein. In summary, the combined results indicated that GHGT-17 exhibits promise as a prospective potential novel drug candidate worthy of further investigation for its potential application in lung cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Implementing the concept of turning waste into treasure, the conversion of biomass waste into high-value carbon materials, especially carbon dots (CDs), has pointed out a new direction for disease diagnosis, tumor treatment, and other aspects. In this work, we have reported the GL-CDs(Fe) via a simple synthesis route exploiting Ganoderma lucidum waste as the precursor. Thanks to their excellent optical property and peroxidase mimetic activity, a novel GL-CDs(Fe)-based ratio fluorescence/colorimetric/smartphone triple mode sensing platform is cleverly fabricated for glucose determination with the LOD of 0.28, 0.37, and 0.52 μΜ separately. Especially, this triple mode biosensor is successfully utilized for glucose detection in serum samples with the relative error of less than ±8 % compared with clinical reports. Surprisingly, the GL-CDs(Fe) also presents immense application prospects in high-level anti-counterfeiting aspects due to their excellent luminescent properties, high water-solubility, and easy availability. Furthermore, GL-CDs(Fe) can catalyze excessive H 2 O 2 inside tumor cells to produce massive hydroxyl radicals (· OH) which break down the redox levels of cancer cells and thereby eliminate tumor cells. Thus, this integrated "Three-in-One" multifunctional platform based on GL-CDs(Fe) unveils enormous research and application prospects for bio-sensing, anti-counterfeiting, cancer treatment. [Display omitted] • GL-CDs(Fe) with ideal optical and peroxidase-like property was derived from biomass waste. • A novel GL-CDs(Fe)-based triple mode sensing platform was fabricated for glucose analysis. • GL-CDs(Fe) was also used for anti-counterfeiting ink and anticancer cell effect. [ABSTRACT FROM AUTHOR]

[Display omitted] • 41 novel FAK covalent inhibitors were synthesized. • Compound 11w displayed highest inhibition of FAK and tumor cells. • 11w inhibited the clone formation and migration of tumor cells, inducing apoptosis. • 11w covalently inhibited the autophosphorylation of FAK in a dose-dependent manner. • 11w showed adequate oral bioavailability and significant antitumor efficacy in vivo. Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC 50 value of 35 nM and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC 50 values of 0.41, 0.01 and 0.11 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G 2 /M phase, inducing tumor cell apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK. [ABSTRACT FROM AUTHOR]

Objective. To study the clinical efficacy of modified Yiwei Shengyang decoction combined with FOLFOX4 chemotherapy regimen in the treatment of advanced gastric cancer and its effect on tumor marker levels. Methods. A total of 106 patients with advanced gastric cancer who were treated in our hospital from September 2019 to September 2021 were recruited and assigned via random number allocation to receive either FOLFOX4 chemotherapy (control group) or modified Yiwei Shengyang decoction plus FOLFOX4 chemotherapy (observation group). Outcome measures included clinical efficacy and tumor marker levels. Results. Modified Yiwei Shengyang decoction plus FOLFOX4 chemotherapy was associated with a significantly higher efficacy (86.79%, including 22 (41.51%) cases of complete response (CR), 24 (45.28%) cases of partial response (PR), 6 (11.32%) cases of stable disease (SD), and 1 (1.89%) case of progressive disease (PD)) compared to FOLFOX4 chemotherapy alone (47.16%, including 10 (18.87%) cases of CR, 15 (28.30%) cases of PR, 21 (39.62%) cases of SD, and 7 (13.21%) cases of PD) (P < 0.05). There was no significant difference in the levels of CEA and CA19-9 between the two groups before treatment (P > 0.05). Modified Yiwei Shengyang decoction plus FOLFOX4 chemotherapy resulted in significantly lower levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) (2.08 ± 0.47, 15.12 ± 6.74) compared to FOLFOX4 chemotherapy alone (5.46 ± 1.84, 31.82 ± 7.48) (P < 0.05). Conclusion. Modified Yiwei Shengyang decoction plus FOLFOX4 chemotherapy regimen is effective in the treatment of advanced gastric cancer. It regulates the levels of various serum tumor markers in patients and controls the disease, so it is worthy of clinical application and promotion. [ABSTRACT FROM AUTHOR]

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics. [ABSTRACT FROM AUTHOR]

Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs. [ABSTRACT FROM AUTHOR]

The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives. [ABSTRACT FROM AUTHOR]

The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC 50 = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo. [Display omitted] • Eleven diterpenoids were obtained from the SFE extract of C. crassifolius roots. • Chettaphanin II showed the strongest antitumor activity against A549 cells. • Chettaphanin II inhibited A549 cell proliferation and arrested cells in G2/M-phase. • Chettaphanin II induced A549 cell apoptosis by inhibiting PI3K/AKT/mTOR pathway. • Chettaphanin II significantly inhibited the growth of tumor tissue in nude mice. [ABSTRACT FROM AUTHOR]

• A new anthrahydrazone ligand (9-THA) and its three metal complexes were synthesized. • The tested cancer cell lines were most sensitive to the Cu(II) complex, 9-THA-Cu. • 9-THA-Cu could bind with DNA in an intercalative mode by its planar structure. • The Cu(II) center play a key role to exert anticancer activity and induce apoptosis. In the present study, we synthesized and extensively characterized a novel ligand, 9-THA, based on 9-benzothiazolanthrahydrazone, along with its three corresponding transition metal complexes: 9-THA-Co (1), 9-THA-Ni (2), and 9-THA-Cu (3). The crystallographic analysis revealed distinct coordination geometries - six-coordinate for 9-THA-Co and 9-THA-Ni, binding three and two 9-THA ligands, respectively, and four-coordinate for 9-THA-Cu, binding one 9-THA ligand. In vitro anticancer screening demonstrated that 9-THA-Cu exhibited significant growth inhibition in HeLa-229, NCI-H460, and SK-OV-3 cancer cells with IC 50 values of 12.10 ± 0.54, 12.12 ± 0.58, and 17.65 ± 0.66 μM, respectively. Moreover, it displayed comparable cytotoxicity to cisplatin on HL-7702 normal liver cells. In contrast, 9-THA and 9-THA-Co/9-THA-Ni did not exhibit significant growth inhibition in the tested cancer cells, suggesting that Cu(II) played a pivotal role in its anticancer mechanism. Further investigation revealed the intercalative DNA binding mode of 9-THA-Cu by UV–Vis and fluorescent spectral analyses. It also exhibited competitive binding with two typical DNA intercalators, Gel-red (GR) and ethidium bromide (EB). Cell cycle and cell apoptosis experiments indicated that 9-THA-Cu at a concentration of 22 μM could induce cell cycle arrest in the S phase in 40 % of HeLa-229 cancer cells. Simultaneously, it induced 33.2 % apoptosis in HeLa-229 cells, suggesting that 9-THA-Cu may employ multiple mechanisms to exert its anticancer effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) has been documented in many malignancies as participating in the progression of cancer cells. Here, we present a novel EGFR tyrosine kinase inhibitor, ZZC4, and examine its effect on cancer cell proliferation, migration, and tumor-bearing xenograft models. The antiproliferative effect of ZZC4 was assessed in vitro by MTT assay, colony formation, and wound healing assay and in vivo with tumor-bearing xenograft nude mice. Further, Western blotting analysis and computational network pharmacology were used to explore and understand the mechanism of ZZC4. The results showed that ZZC4 potently inhibited the proliferation of lung, breast, and melanoma cells, and was more sensitive to lung cancer cells HCC827, H1975, and breast cancer cell T47D. In vitro findings were corroborated in vivo as results showed the suppressive effect of ZZC4 on HCC827 and H1975 tumor growth. Western blotting analysis confirmed that ZZC4 is an effective inhibitor of the EGFR pathways as it down-regulated p-EGFR, p-Akt, and p-MAPK. Computational molecular docking confirmed the strong binding affinity between ZZC4 and EGFR. Moreover, network pharmacology suggested that ZZC4 might play a suppressive role in the progression of malignancies with EGFR/PI-3K/Akt axis dysregulation or in cancer-related drug resistance. Our study showed that ZZC4 is an anticancer drug candidate. • ZZC4 is a novel purine-containing EGFR tyrosine kinase inhibitor. • ZZC4 potently inhibited the proliferation and tumor growth of lung and breast cancer cells. • Network pharmacology can be used the determine the possible target of small molecules drugs. [ABSTRACT FROM AUTHOR]

Polyrhachis vicina Roger (P. vicina), a traditional Chinese medicinal animal, has been used to treat rheumatoid arthritis, hepatitis, cancer, and other conditions. Due to its anti-inflammatory properties, our previous pharmacological investigations have demonstrated that it is effective against cancer, depression, and hyperuricemia. Nevertheless, the key active components and targets of P. vicina in cancers are still unexplored. The study aimed to evaluate the pharmacological treatment mechanism of the active fraction of P. vicina (AFPR) in treating colorectal cancer (CRC) and to further reveal its active ingredients and key targets. To examine the inhibitory impact of AFPR on CRC growth, tumorigenesis assays, cck-8 assays, colony formation assays, and MMP detection were utilized. The primary components of AFPR were identified by GC-MS analysis. The network pharmacology, molecular docking, qRT-PCR, western blotting, CCK-8 assays, colony formation assay, Hoechst staining, Annexin V-FITC/PI double staining, and MMP detection were performed to pick out the active ingredients and potential key targets of AFPR. The function of Elaidic acid on necroptosis was investigated through siRNA interference and the utilization of inhibitors. Elaidic acid's effectiveness to suppress CRC growth in vivo was assessed using a tumorigenesis experiment. Studies confirmed that AFPR prevented CRC from growing and evoked cell death. Elaidic acid was the main bioactive ingredient in AFPR that targeted ERK. Elaidic acid greatly affected the ability of SW116 cells to form colonies, produce MMP, and undergo necroptosis. Additionally, Elaidic acid promoted necroptosis predominantly by activating ERK/RIPK1/RIPK3/MLKL. According to our findings, Elaidic acid is the main active component of AFPR, which induced necroptosis in CRC through the activation of ERK. It represents a promising alternative therapeutic option for CRC. This work provided experimental support for the therapeutic application of P. vicina Roger in the treatment of CRC. [Display omitted] • The active fraction of Polyrhachis vicina Roger (AFPR) inhibited CRC growth in vivo and in vitro. • Network pharmacology and molecular docking predicted ERK might be the key target of AFPR in antagonizing CRC. • Elaidic acid was a key active component of AFPR and induced necroptosis. • Elaidic acid induced necroptosis via ERK activation. [ABSTRACT FROM AUTHOR]

Ginsenoside Rg1 (Rg1) is one of the main active components in Panax ginseng C. A. Meyer (ginseng), which has been widely used to delay senescence or improve health conditions for more than 2000 years. Increasing studies have revealed that Rg1 could regulate cell proliferation and differentiation, as well as anti-inflammatory and anti-apoptotic effects, and might have protective effects on many chronic kidney diseases. Diabetic nephropathy (DN) is one of the most dangerous microvascular complications of diabetes and is the leading cause of end-stage renal disease worldwide. However, the role and mechanism of Rg1 against high-glucose and high-fat-induced glomerular fibrosis in DN are not clear. This study aimed to investigate the protective effect of Rg1 on DN and its possible mechanism. The type 2 diabetes mellitus (T2DM) mice models were established with a high-fat diet (HFD) combined with an intraperitoneal injection of streptozotocin (STZ). Urine protein and serum biochemical indexes were detected by corresponding kits. The kidney was stained with H&E, PAS, and Masson to observe the pathological morphology, glycogen deposition, and fibrosis. The expression of CD36 and p-PLC in the kidney cortex was detected by IHC. The expressions of FN and COL4 were detected by IF. Western blot and PCR were performed to examine protein and mRNA expressions of kidney fibrosis and TRPC6/NFAT2-related pathways in DN mice. Calcium imaging was used to examine the effect of Rg1 on [Ca2+] i in PA + HG-induced human mesangial cells (HMCs). Visualization of the interaction between Rg1 and CD36 was detected by molecular docking. Rg1 treatment for 8 weeks could prominently decrease urinary protein, serum creatinine, and urea nitrogen and downgrade blood lipid levels and renal lipid accumulation in T2DM mice. The pathological results indicated that Rg1 treatment attenuated renal pathological injury and glomerular fibrosis. The further results demonstrated that Rg1 treatment remarkably decreased the expressions of CD36, TRPC6, p-PLC, CN, NFAT2, TGF-β, p-Smad2/3, COL4, and FN in renal tissues from T2DM mice. Calcium imaging results found that Rg1 downgraded the base levels of [Ca2+] i and ΔRatioF340/F380 after BAPTA and CaCl 2 treatment. Molecular docking results showed that Rg1 could interact with CD36 with a good affinity. These results revealed that Rg1 could ameliorate renal lipid accumulation, pathological damage, and glomerular fibrosis in T2DM mice. The mechanism may be involved in reducing the overexpression of CD36 and inhibiting the TRPC6/NFAT2 signaling pathway in renal tissues of T2DM mice. [Display omitted] • Rg1 treatment ameliorates glomerular fibrosis and diabetic nephropathy in T2DM mice. • Rg1 treatment decreases the levels of blood lipids and renal DAG and IP3 in T2DM mice. • Rg1 treatment inhibits CD36 expression and PLC activation in T2DM mice. • Rg1 treatment inhibits TRPC6/CN/NFAT2 signaling in T2DM mice. [ABSTRACT FROM AUTHOR]